Mouse bone marrow-derived mesenchymal stem cells inhibit leukemia/lymphoma cell proliferation in vitro and in a mouse model of allogeneic bone marrow transplant

Song,Ningxia; Gao,Lei; Qiu,Huiying; Huang,Chongmei; Cheng,Hui; Zhou,Hong; Lv,Shuqing; Chen,Li; Wang,Jianmin

doi:10.3892/ijmm.2015.2191

Mouse bone marrow-derived mesenchymal stem cells inhibit leukemia/lymphoma cell proliferation in vitro and in a mouse model of allogeneic bone marrow transplant

Authors:
- Ningxia Song
- Lei Gao
- Huiying Qiu
- Chongmei Huang
- Hui Cheng
- Hong Zhou
- Shuqing Lv
- Li Chen
- Jianmin Wang
View Affiliations

Affiliations: Department of Hematology, Institute of Hematology, PLA, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China
Published online on: April 21, 2015 https://doi.org/10.3892/ijmm.2015.2191
Pages: 139-149
Copyright: © Song et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The allogeneic hematopoietic stem cell (HSC) transplantation of mesenchymal stem cells (MSCs) contributes to the reconstitution of hematopoiesis by ameliorating acute graft‑versus‑host disease (aGVHD). However, the role of MSCs in graft‑versus‑leukemia remains to be determined. In the present study, we co‑cultured C57BL/6 mouse bone marrow (BM)‑derived MSCs with A20 murine B lymphoma, FBL3 murine erythroleukemia and P388 murine acute lymphocytic leukemia cells. Cell proliferation, apoptosis, cell cycle progression and the amount of cytokine secretion were then measured using a Cell Counting kit‑8, Annexin V/propidium iodide staining, flow cytometry and ELISA, respectively. We also established a model of allogeneic bone marrow transplantation (BMT) using BALB/c mice. Following the administration of A20 cells and MSCs, we recorded the symptoms and the survival of the mice for 4 weeks, assessed the T cell subsets present in peripheral blood, and, after the mice were sacrifice, we determined the infiltration of MSCs into the organs by histological staining. Our results revealed that the MSCs inhibited the proliferation of the mouse lymphoma and leukemia cells in vitro, leading to cell cycle arrest and reducing the secretion of interleukin (IL)‑10. In our model of allogeneic BMT, the intravenous injection of MSCs into the mice injected wth A20 cells decreased the incidence of lymphoma, improved survival, increased the fraction of CD3+CD8+ T cells, decreased the fraction of CD3+CD4+ T cells and CD4+CD25+ T cells in peripheral blood, and ameliorated the manifestation of aGVHD. The results from the present study indicate that MSCs may be safe and effective when used in allogeneic BMT for the treatment of hemotological malignancies.

View Figures

View References

1	Sorrentino A, Ferracin M, Castelli G, Biffoni M, Tomaselli G, Baiocchi M, Fatica A, Negrini M, Peschle C and Valtieri M: Isolation and characterization of CD146+ multipotent mesenchymal stromal cells. Exp Hematol. 36:1035–1046. 2008. View Article : Google Scholar : PubMed/NCBI
2	Le Blanc K, Samuelsson H, Gustafsson B, Remberger M, Sundberg B, Arvidson J, Ljungman P, Lönnies H, Nava S and Ringdén O: Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells. Leukemia. 21:1733–1738. 2007. View Article : Google Scholar : PubMed/NCBI
3	Herrmann RP and Sturm MJ: Adult human mesenchymal stromal cells and the treatment of graft versus host disease. Stem Cells Cloning. 7:45–52. 2014.PubMed/NCBI
4	Shlomchik WD: Graft-versus-host disease. Nat Rev Immunol. 7:340–352. 2007. View Article : Google Scholar : PubMed/NCBI
5	Otsu K, Das S, Houser SD, Quadri SK, Bhattacharya S and Bhattacharya J: Concentration-dependent inhibition of angiogenesis by mesenchymal stem cells. Blood. 113:4197–4205. 2009. View Article : Google Scholar :
6	Khakoo AY, Pati S, Anderson SA, et al: Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi’s sarcoma. J Exp Med. 203:1235–1247. 2006. View Article : Google Scholar : PubMed/NCBI
7	Zhu Y, Sun Z, Han Q, et al: Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1. Leukemia. 23:925–933. 2009. View Article : Google Scholar : PubMed/NCBI
8	Wang PP, Xie DY, Liang XJ, Peng L, Zhang GL, Ye YN, Xie C and Gao ZL: HGF and direct mesenchymal stem cells contact synergize to inhibit hepatic stellate cells activation through TLR4/NF-kB pathway. PLoS One. 7:e434082012. View Article : Google Scholar : PubMed/NCBI
9	Menge T, Gerber M, Wataha K, Reid W, Guha S, Cox CS Jr, Dash P, Reitz MS Jr, Khakoo AY and Pati S: Human mesenchymal stem cells inhibit endothelial proliferation and angiogenesis via cell-cell contact through modulation of the VE-Cadherin/β-catenin signaling pathway. Stem Cells Dev. 22:148–157. 2013. View Article : Google Scholar :
10	Galiè M, Konstantinidou G, Peroni D, et al: Mesenchymal stem cells share molecular signature with mesenchymal tumor cells and favor early tumor growth in syngeneic mice. Oncogene. 27:2542–2551. 2008. View Article : Google Scholar
11	Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R and Weinberg RA: Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 449:557–563. 2007. View Article : Google Scholar : PubMed/NCBI
12	Cirone M, Lucania G, Aleandri S, Borgia G, Trivedi P, Cuomo L, Frati L and Faggioni A: Suppression of dendritic cell differentiation through cytokines released by Primary Effusion Lymphoma cells. Immunol Lett. 120:37–41. 2008. View Article : Google Scholar : PubMed/NCBI
13	Wang L, Zhao Y, Qian J, Sun L, Lu Y, Li H, Li Y, Yang J, Cai Z and Yi Q: Toll-like receptor-4 signaling in mantle cell lymphoma: effects on tumor growth and immune evasion. Cancer. 119:782–791. 2013. View Article : Google Scholar
14	Shen L, Chiang AK, Liu WP, Li GD, Liang RH and Srivastava G: Expression of HLA class I, beta(2)-microglobulin, TAP1 and IL-10 in Epstein-Barr virus-associated nasal NK/T-celllymphoma: Implications for tumor immune escape mechanism. Int J Cancer. 92:692–696. 2001. View Article : Google Scholar : PubMed/NCBI
15	Djouad F, Plence P, Bony C, Tropel P, Apparailly F, Sany J, Noël D and Jorgensen C: Immunosuppressive effect of mesen-chymal stem cells favors tumor growth in allogeneic animals. Blood. 102:3837–3844. 2003. View Article : Google Scholar : PubMed/NCBI
16	Chen WJ, Huang JW, Niu CC, Chen LH, Yuan LJ, Lai PL, Yang CY and Lin SS: Use of fluorescence labeled mesenchymal stem cells in pluronic F127 and porous hydroxyapatite as a bone substitute for posterolateral spinal fusion. J Orthop Res. 27:1631–1636. 2009. View Article : Google Scholar : PubMed/NCBI
17	Wang Y, Chen X, Cao W and Shi Y: Plasticity of mesenchymal stem cells in immunomodulation: Pathological and therapeutic implications. Nat Immunol. 15:1009–1016. 2014. View Article : Google Scholar : PubMed/NCBI
18	Dalal J, Gandy K and Domen J: Role of mesenchymal stem cell therapy in Crohn’s disease. Pediatr Res. 71:445–451. 2012. View Article : Google Scholar : PubMed/NCBI
19	Cohen JA: Mesenchymal stem cell transplantation in multiple sclerosis. J Neurol Sci. 333:43–49. 2013. View Article : Google Scholar : PubMed/NCBI
20	Lu YR, Yuan Y, Wang XJ, et al: The growth inhibitory effect of mesenchymal stem cells on tumor cells in vitro and in vivo. Cancer Biol Ther. 7:245–251. 2008. View Article : Google Scholar
21	Ilmer M, Vykoukal J, Recio Boiles A, Coleman M and Alt E: Two sides of the same coin: Stem cells in cancer and regenerative medicine. FASEB J. 28:2748–2761. 2014. View Article : Google Scholar : PubMed/NCBI
22	Ramasamy R, Lam EW, Soeiro I, Tisato V, Bonnet D and Dazzi F: Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: Impact on in vivo tumor growth. Leukemia. 21:304–310. 2007. View Article : Google Scholar
23	Elpek KG, Lacelle C, Singh NP, Yolcu ES and Shirwan H: CD4⁺CD25⁺ T regulatory cells dominate multiple immune evasion mechanisms in early but not late phases of tumor development in a B cell lymphoma model. J Immunol. 178:6840–6848. 2007. View Article : Google Scholar : PubMed/NCBI
24	Zhu W, Xu W, Jiang R, Qian H, Chen M, Hu J, Cao W, Han C and Chen Y: Mesenchymal stem cells derived from bone marrow favor tumor cell growth in vivo. Exp Mol Pathol. 80:267–274. 2006. View Article : Google Scholar
25	Djouad F, Bony C, Apparailly F, Louis-Plence P, Jorgensen C and Noël D: Earlier onset of syngeneic tumors in the presence of mesenchymal stem cells. Transplantation. 82:1060–1066. 2006. View Article : Google Scholar : PubMed/NCBI
26	Baron F, Lechanteur C, Willems E, et al: Cotransplantation of mesenchymal stem cells might prevent death from graft-versus- host disease (GVHD) without abrogating graft-versus-tumor effects after HLA-mismatched allogeneic transplantation following nonmyeloablative conditioning. Biol Blood Marrow Transplant. 16:838–847. 2010. View Article : Google Scholar : PubMed/NCBI
27	Le Blanc K, Rasmusson I, Sundberg B, Götherström C, Hassan M, Uzunel M and Ringdén O: Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 363:1439–1441. 2004. View Article : Google Scholar : PubMed/NCBI
28	Ning H, Yang F, Jiang M, et al: The correlation between cotrans-plantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients: Outcome of a pilot clinical study. Leukemia. 22:593–599. 2008. View Article : Google Scholar : PubMed/NCBI